The present invention relates to new 3-pyrroloimidazole derivatives, to pharmaceutical compositions comprising them, to the preparation and use thereof, especially as tumour- and cancer-lysing and more especially as antibiotic, very especially antibacterial, medicaments.
Cancer and tumour diseases are among civilisation""s problematic clinical entities. In many cases, the tumour tissue has to be surgically removed and/or treated by chemotherapy. Long-term patient survival is, however, very uncertain. Moreover, chemotherapy and surgical treatment frequently involve pain and other problems for the cancer patient. The provision of new, complementary medicaments for the treatment of tumour and cancer diseases is, therefore, of great interest. Also, it can be assumed, in the light of the general increase in the formation of resistance in micro-organisms and bacteria, that there exists a need for new and similarly active, or even more active, antibiotics.
The problem of the present invention was accordingly to provide new active ingredients having improved and/or complementary action in the prophylaxis and/or therapy of cancer and tumours and/or especially strong antibiotic, more especially antibacterial, activity in the prophylaxis and/or combating/therapy of infections by micro-organisms.
The problems are solved by provision of 3-pyrroloimidazole derivatives of the general formula (I): 
wherein
the imidazole radical is an optionally substituted imidazole ring, which may also be present in salt form,
X, Y, A and B are, each independently of the others, carbon or nitrogen atoms, X, Y, A and B preferably being carbon atoms,
the radicals Z can denote, each independently of the others, a hydrogen atom, a halogen atom, a pseudohalogen, an optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl or alkoxy radical and/or an optionally substituted ring, to which one or two further, optionally substituted rings may be fused, and/or at least two of the radicals Z may be part of an optionally substituted ring, to which one or two further, optionally substituted rings may be fused. The radicals Z preferably are, each independently of the others, a hydrogen atom, a halogen atom or a pseudohalogen, more preferably a hydrogen atom, fluorine, chlorine, bromine or iodine, most preferably a hydrogen atom.
Preferably, the radicals Zxe2x80x94Axe2x95x90Bxe2x80x94Z together have the formula 
wherein R1 is a substituent, preferably a group of formula xe2x80x94Gxe2x80x94 substituted C1-C6alkyl, such as xe2x80x94Gxe2x80x94C1-C6alkyl-aryl, especially xe2x80x94G-benzyl; xe2x80x94G-aryl; xe2x80x94Gxe2x80x94C1-C6alkyl; xe2x80x94G-cycloalkyl; xe2x80x94G-heterocycloalkyl; xe2x80x94Gxe2x80x94C1-C6alkyl-heteroaryl, wherein G is CH2, O, N or S, preferably O, or R1 is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkenyl, and wherein the radicals Z bonded to N and Y are, each independently of the other, C1-C6alkyl radicals, such as methyl radicals, cycloalkyl radicals or H atoms, preferably H atoms.
Throughout the description and the claims, the expression xe2x80x9calkylxe2x80x9d can denote, for example, a C1-50alkyl group, preferably a C1-12alkyl, especially a C1-6alkyl group; for example, an alkyl group may be a methyl, ethyl, propyl, isopropyl or butyl group;
the expression xe2x80x9calkxe2x80x9d, for example in the expression xe2x80x9calkoxyxe2x80x9d, is defined as for xe2x80x9calkylxe2x80x9d;
xe2x80x9caromatic compoundsxe2x80x9d or xe2x80x9carylsxe2x80x9d or corresponding radicals are, for example, substituted or optionally unsubstituted phenyl, benzyl, naphthyl, biphenyl or anthracene groups or aromatic heterocycles having 5 or 6 ring atoms;
the expression xe2x80x9carxe2x80x9d, for example in the expressions xe2x80x9caralkylxe2x80x9d, xe2x80x9caralkenylxe2x80x9d, xe2x80x9caralkynylxe2x80x9detc. and xe2x80x9ccycloaralkylxe2x80x9d, xe2x80x9ccycloaralkenylxe2x80x9d, xe2x80x9ccycloaralkynylxe2x80x9d etc., is defined as for xe2x80x9carylxe2x80x9d;
the expression xe2x80x9calkenylxe2x80x9d can denote, for example, a C2-10alkenyl group, preferably a C2-6alkenyl group, which has the double bond(s) at any desired location and may be unsubstituted or substituted; for example, an ethenyl, propenyl, isopropenyl or butenyl group;
the expression xe2x80x9calkynylxe2x80x9d can denote, for example, a C2-10alkynyl group, preferably a C2-6alkynyl group, which has the triple bond(s) at any desired location and may be unsubstituted or substituted; for example, an ethynyl, propynyl, isopropynyl or butynyl group;
the expression xe2x80x9ccycloalkylxe2x80x9d can denote, for example, an optionally substituted carbocycle having from 3 to 20 C atoms, preferably having from 5 to 15 C atoms and especially having 5 or 6 C atoms, which has no multiple bond in the carbocycle;
the expression xe2x80x9ccycloalkenylxe2x80x9d can denote, for example, an optionally substituted carbocycle having from 3 to 20 C atoms, preferably having from 5 to 15 C atoms and especially having 5 or 6 C atoms, which has at least one double bond in the carbocycle;
the expression xe2x80x9ccycloalkynylxe2x80x9d can denote, for example, an optionally substituted carbocycle having from 3 to 20 C atoms, preferably having from 5 to 15 C atoms and especially having 9 or 10 C atoms, which has at least one triple bond in the carbocycle;
the expression xe2x80x9calkoxyxe2x80x9d can denote, for example, a group of formula xe2x80x94O-alkyl, xe2x80x94O-alkenyl, xe2x80x94O-alkynyl, xe2x80x94O-cycloalkyl, xe2x80x94O-cycloalkenyl, xe2x80x94O-cycloalkynyl or xe2x80x94O-aryl,
the expression xe2x80x9cheteroaroylxe2x80x9d can denote, for example, 5-6-membered heterocyclic aromatic heterocycles having 1, 2 or 3 hetero atoms, for example substituted (as defined hereinbelow) pyrrole, furan, thiophene pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole 1,2,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, tetrazole, pyridine, pyrylium, thiapyrylium, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, indole, coumarone, thio-naphthene, carbazole, bibenzofuran, dibenzothiophene, 1H-indazole, indoxazole, benzo[d]isothiazole, anthranile, benzimidazole, benzoxazole, benzothiazole, benzotriazole, quinoline, isoquinoline, benzopyrylium, thiabenzopyrylium, acridine, benzo[g]quinoline, benzo[g]isoquinoline, benzo[c]quinoline, cinnoline, phthalazine, quinazoline, quinoxaline, phenazine, benzo[g]cinnoline, benzo[g]quin-azoline, benzo[g]quinoxaline, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, 1,7-phenanthroline, 1,8-phenanthroline, 1,9-phenanthroline,1,10-phenanthroline, indolizine, 4H-quinolizine, carboline, ergoline, purine, pteridine, alloxazine or flavin;
the expression xe2x80x9csubstitutedxe2x80x9d or substituent can be defined as follows: xe2x80x94H, xe2x80x94OH, xe2x80x94Ra, xe2x80x94O-alkyl, xe2x80x94O-aryl, xe2x80x94O-heteroaroyl, xe2x80x94O-heterocycle, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N3, xe2x80x94CNRaNRbRc, xe2x80x94NRaRb, NRaRbRc+, fluorine, chlorine, bromine, a-, b-, to w-amino acid esters, xe2x80x94NRaCORb, xe2x80x94NRaCOXRb(X=xe2x80x94O, xe2x80x94NR, xe2x80x94PO0,2,3,4R, xe2x80x94SO0,1,2,4,R or xe2x80x94NRaNRbRc), xe2x80x94CORa, xe2x80x94COORa, xe2x80x94OCOORa, xe2x80x94CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NRcCONRaRb, xe2x80x94Raxe2x80x94Oxe2x80x94Rb, xe2x80x94Rcxe2x80x94NRaRb, xe2x80x94Raxe2x80x94Sxe2x80x94Rb, xe2x80x94Raxe2x80x94SOxe2x80x94Rb, xe2x80x94Raxe2x80x94S(O)2xe2x80x94Rbxe2x80x94ORaxe2x80x94Oxe2x80x94Rb, xe2x80x94NRaRbxe2x80x94Oxe2x80x94Rc, xe2x80x94SO2Ra, xe2x80x94SO1,2,3,4Raxe2x80x94Oxe2x80x94Rb, xe2x80x94CORaxe2x80x94ORb, xe2x80x94COORaxe2x80x94Oxe2x80x94Rb, xe2x80x94OCORa, xe2x80x94Oxe2x80x94Rb, xe2x80x94OCOORaxe2x80x94Oxe2x80x94Rb, xe2x80x94NRbCORaxe2x80x94Oxe2x80x94Rb, xe2x80x94CONRaRbxe2x80x94Oxe2x80x94Rc, xe2x80x94OCONRaRbxe2x80x94Oxe2x80x94Rc, xe2x80x94NRcCONRaRbxe2x80x94Oxe2x80x94Rd, xe2x80x94NRaCORbxe2x80x94Oxe2x80x94Rc, xe2x80x94ORaxe2x80x94Sxe2x80x94Rb, xe2x80x94NRaRbxe2x80x94Sxe2x80x94Rc, xe2x80x94SO1,2,3,4Raxe2x80x94Sxe2x80x94Rb, xe2x80x94CORaxe2x80x94Sxe2x80x94Rb, xe2x80x94OCORaxe2x80x94Sxe2x80x94Rb, xe2x80x94OCORaxe2x80x94Sxe2x80x94Rb, xe2x80x94NRaCORbxe2x80x94Sxe2x80x94Rc, xe2x80x94CONRaRbxe2x80x94Sxe2x80x94Rc, xe2x80x94NRaCONRbRcxe2x80x94Sxe2x80x94Rd, xe2x80x94ORaxe2x80x94NRbRc, xe2x80x94NRaRbxe2x80x94NRcRd, xe2x80x94SO1,2,3,4Rbxe2x80x94NRbRc, xe2x80x94CORaxe2x80x94NRbRc, xe2x80x94COORaxe2x80x94NRbRc, xe2x80x94OCORaxe2x80x94NRbRc, xe2x80x94OCOORaxe2x80x94NRbRc, xe2x80x94NRaCONRbRcxe2x80x94NRdRe, xe2x80x94NRaCOORbxe2x80x94NRcRd, xe2x80x94OCONRaRbxe2x80x94NRcRd, xe2x80x94NRaxe2x80x94CONRbRcxe2x80x94NHRd, xe2x80x94NRaCOORbxe2x80x94NRcxe2x80x94Rd, xe2x80x94POORaORb, xe2x80x94NRcPOORaORb, xe2x80x94SO2NRaRb, xe2x80x94SONRaNRbRc, xe2x80x94SNRaRbNRcRd, xe2x80x94NRaSO2Rb, xe2x80x94NRaSONRbRc, xe2x80x94NRaSNRbNRcRd, xe2x80x94NRaSO2NRbRe, xe2x80x94NRaSONRbNRcRd or xe2x80x94NRaSNRbNRcNRdRe, it being possible for the substituents to be, for example, bonded by way of a double bond or fused,
wherein Ra, Rb, Rc and Rd may be, each independently of the others, in the form of substituents, as defined above, alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhaloalkyl and or may be a member of a chain corresponding to alkylene, alkenylene, alkynylene, aroylene, heteroaroylene, heterocyclene, aralkylene, aralkenylene or perhaloalkylene; Ra, Rb, Rc and Rd may themselves be substituted, for example by alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhalo-alkyl, the substituents of Ra, Rb, Rc and Rd, however, being preferably unsubstituted; it being clear, in the above formulae, from the valency of the atoms to which Ra, Rb, Rc and Rd are bonded, when Ra, Rb, Rc and Rd are substituents or when they are chain members (for example, in xe2x80x94CORaxe2x80x94NRbRc, Ra is a chain member as carbon is at most tetravalent);
the expression xe2x80x9cringxe2x80x9d can denote an aromatic, a cycloalkyl, cycloalkenyl, cycloalkynyl or heterocyclic ring.
The expression xe2x80x9cheterocyclic ringxe2x80x9d can denote, for example, a cycloalkyl, cycloalkenyl, cycloalkynyl or aromatic ring which, besides C atoms, contains 1, 2, 3 or 4 N, S or O atoms, with preference being given to 5- or 6-membered rings containing 1 or 2 N atoms.
The imidazole ring can be, for example, unsubstituted or can have, for example, 1, 2, 3 or 4, preferably 1, 2, or 3, substituent(s) selected from halogen atoms, pseudohalogens, substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl, alkoxy radicals and non-aromatic or aromatic or partially aromatic heterocyclic radicals, which may be unsubstituted or substituted by one or more substituent(s) selected from xe2x80x94OH, xe2x80x94Ra, xe2x80x94O-alkyl, xe2x80x94O-aryl, xe2x80x94O-heteroaroyl, an xe2x80x94O-heterocycle, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N3, xe2x80x94CNRaNRbRc, xe2x80x94NRaRb, NRaRbRc+, fluorine, chlorine, bromine, a-, b-, to w-amino acid esters, xe2x80x94NRaCORb, xe2x80x94NRaCOXRb (X=xe2x80x94O, xe2x80x94NR, xe2x80x94PO0,2,3,4R, xe2x80x94SO0,1,2,4,R, xe2x80x94NRaNRbRc), xe2x80x94CORa, xe2x80x94COORa, xe2x80x94OCOORa, CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NRcCONRaRb, xe2x80x94Raxe2x80x94Oxe2x80x94Rb, xe2x80x94Rcxe2x80x94NRaRb, xe2x80x94Raxe2x80x94Sxe2x80x94Rb, xe2x80x94Raxe2x80x94SOxe2x80x94Rb, xe2x80x94Raxe2x80x94S(O)2xe2x80x94Rb, xe2x80x94ORaxe2x80x94Oxe2x80x94Rb, xe2x80x94NRaRbxe2x80x94Oxe2x80x94Rc, xe2x80x94SO2Ra, xe2x80x94SO1,2,3,4Raxe2x80x94Oxe2x80x94Rb, xe2x80x94CORaxe2x80x94ORb, xe2x80x94COORaxe2x80x94Oxe2x80x94Rb, xe2x80x94OCORaxe2x80x94Oxe2x80x94Rb, xe2x80x94OCOORaxe2x80x94Oxe2x80x94Rb, xe2x80x94NRbCORaOxe2x80x94Rb, xe2x80x94CONRaRbxe2x80x94Oxe2x80x94Rc, xe2x80x94OCONRaRbxe2x80x94Oxe2x80x94Rc, xe2x80x94NRcCONRaRbxe2x80x94Oxe2x80x94Rd, xe2x80x94NRaCORbxe2x80x94Oxe2x80x94Rc, xe2x80x94ORaxe2x80x94Sxe2x80x94Rb, xe2x80x94NRaRbxe2x80x94Sxe2x80x94Rc, xe2x80x94SO1,2,3,4Raxe2x80x94Sxe2x80x94Rb, xe2x80x94CORaxe2x80x94Sxe2x80x94Rb, xe2x80x94OCORaxe2x80x94Sxe2x80x94Rb, xe2x80x94OCORaxe2x80x94Sxe2x80x94Rb, xe2x80x94NRaCORbxe2x80x94Sxe2x80x94Rc, xe2x80x94CONRaRbxe2x80x94Sxe2x80x94Rc, xe2x80x94NRaCONRbRcxe2x80x94Sxe2x80x94Rd, xe2x80x94ORaxe2x80x94NRbRc, xe2x80x94NRaRbxe2x80x94NRcRd, xe2x80x94SO1,2,3,4Rbxe2x80x94NRbRc, xe2x80x94CORaxe2x80x94NRbRc, xe2x80x94COORaxe2x80x94NRbRc, xe2x80x94OCORaxe2x80x94NRbRc, xe2x80x94OCOORaxe2x80x94NRbRc, xe2x80x94NRaCONRbRcxe2x80x94NRd, xe2x80x94NRaCOORbxe2x80x94NRcRd, xe2x80x94OCONRaRbxe2x80x94NRdRd, xe2x80x94NRaCONRbRcxe2x80x94NHRd, xe2x80x94NRaCOORbxe2x80x94NRcRd, xe2x80x94POORaORb, xe2x80x94NRcPOORaORb, xe2x80x94SO2NRaRb, xe2x80x94SONRaNRbRc, xe2x80x94SNRaRbNRcRd, xe2x80x94NRaSO2Rb, xe2x80x94NRaSONRbRc, xe2x80x94NRaSNRbNRcRd, xe2x80x94NRaSO2NRb, xe2x80x94NRaSONRbNRc and xe2x80x94NRaSNRbNRcNRd, wherein Ra, Rb, Rc and Rdmay be, each independently of the others, in the form of substituents, as defined above, alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhaloalkyl or may be a member of a chain corresponding to alkylene, alkenylene, alkynylene, aroylene, heteroaroylene, heterocyclene, aralkylene, aralkenylene or perhaloalkylene; Ra, Rb, Rc and Rd may themselves be substituted, for example by alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a hetero-cycle, aralkyl, aralkenyl or by perhaloalkyl, the substituents of Ra, Rb, Rc and Rd, however, being preferably unsubstituted, it being possible for the substituents to be, for example, bonded by way of a double bond or fused.
Preference is given to the imidazole ring being bonded to atom X in formula I by way of its 5-position ring atom. Special preference is given to the imidazole ring having additional substituents in the 1- and/or 4-positions.
Specific examples of substituents on the imidazole ring are cyclohexyl, indanyl, tetrahydronaphthyl, benzylpiperidyl, benzyl, phenethyl, indolyl, methylindolyl, ethylindolyl, 5-(benzyloxy)-1H-pyrrolo[2,3-c]pyridyl, fluorophenyl.
Further preferred substituents can be found in the Examples.
Special preference is given to the imidazole ring being substituted in the 1-position by cycloalkyls having preferably 5, 6 or 7 ring atoms to which aryls or heteroaryls having preferably 5 or 6 ring atoms are fused. Especially preferred heteroaryls are furan and thiophene. The cycloalkyls, aryls and heteroaryls may have 1, 2, 3, 4 or 5 substituents, for example halogens, xe2x80x94CF3, xe2x80x94OMe, xe2x80x94OH, xe2x80x94Me, with preference being given to compounds that are unsubstituted or that have one substituent.
According to a further preferred embodiment, the imidazole ring has, in addition to or alternatively to substitution in the 1-position, a substituent in the 4-position.
That substituent preferably consists of substituted or unsubstituted alkyls, heteroaryls or aryls, with preference being given to heteroaryls or aryls having 5 or 6 ring atoms.
Furthermore, the 3-pyrroloimidazole derivatives may have the following general formulae: 
the 3-pyrroloimidazole derivatives may especially have the following general formulae: 
the 3-pyrroloimidazole derivatives may more especially have the following general formulae: 
wherein the radicals Z are as defined hereinbefore and the radicals R are, each independently of the other(s), a hydrogen atom, a halogen atom, a pseudohalogen, an optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl, aryloxy, aralkyloxy, alkoxy radical, a substituent or a heterocyclic ring, and/or two or more of the radicals R may form, for example a further ring. Preferably, the radicals R are, each independently of the other(s), a hydrogen atom, a halogen atom, a pseudohalogen, especially a hydrogen atom, fluorine, chlorine, bromine or iodine, more especially a hydrogen atom.
According to a preferred embodiment, compounds of formula I wherein Xxe2x95x90Yxe2x95x90Axe2x95x90Bxe2x95x90N are excluded. For example, 2 or 3 of the atoms X, Y, A and B may be N atoms; likewise, for example, 2 or 3 of the atoms X, Y, A and B may be C atoms.
Furthermore, pharmaceutical compositions are disclosed, in accordance with the invention, comprising at least one of the afore-mentioned compounds, optionally in combination with carriers and/or adjuvants and/or excipients customary per se.
The compounds according to the invention have a high level of activity, especially in cancer and tumour prophylaxis and therapy. That activity allows the active ingredients and pharmaceutical compositions according to the invention to be used as chemotherapeutic agents in human and veterinary medicine.
The term xe2x80x9cchemotherapeutic agentsxe2x80x9d is a broad term encompassing substances having a (substantially) selectively damaging action on tumour cells and pathogens. The terms cytostatic agents and antibiotics are also widely used.
The antibiotic activity of the compounds and active ingredients according to the invention and of pharmaceutical compositions comprising them is especially pronounced. It will be clear that the term xe2x80x9cantibioticxe2x80x9d is to be understood in its widest sense and encompasses, for example, antibacterial and antimycotic and/or antifungal action (including action against yeasts).
The compounds or pharmaceutical compositions according to the invention can be used locally or systemically. Systemic administration is understood to mean, for example, intravenous, intrapleural, intraperitoneal, rectal or oral administration or irrigation of body cavities and the urinary bladder. Local administration is understood to mean, for example, subcutaneous, intracutaneous, intratumoral or peritumoral administration, for example in the form of injection solutions, injection suspensions, creams, lotions, gels and ointments.
The life of tumour cells in vitro is significantly shortened by the active ingredients according to the invention compared to controls.
On systemic and local administration, the active ingredients according to the invention have a dose-dependent tumour-lysing action and an especially pronounced antibiotic action. When used therapeutically, the daily dose of active ingredients according to the invention is of the order of from 0.1 to 100 mg/kg of bodyweight, preferably from 2 to 40 mg/kg of bodyweight. In individual cases, the dosage may be higher or lower than that mentioned above.
The active ingredients according to the invention can be used in known mannerxe2x80x94depending upon the individual clinical entityxe2x80x94in a formulation, for example patches, ointments, pastes, gels, creams, soluble powders, lotions, emulsions, sprays, powders, suspensions, suppositories and injection solutions.
The active ingredients according to the invention can be formulated, for example, as injection solutions, by dissolving them, where appropriate with the aid of solubilisers, in dilute physiologically acceptable bases and by being brought into an injectable form having a pH of from 6 to 8, especially from 6.9 to 7.5, by the addition of physiologically acceptable acids.
Examples of physiologically acceptable bases are hydroxides, hydrogen carbonates, carbonates of alkali and alkaline-earth metals, especially of potassium, sodium and calcium.
Examples of physiologically acceptable acids are lactic acid, citric acid, tartaric acid, oxalic acid, malic acid, acetic acid, formic acid, benzoic acid, salicylic acid, hydrochloric acid, sulphuric acid or phosphoric acid.
Excipients may be mixed in with the formulation of active ingredients according to the invention (one or more of which may be used). Such non-toxic and pharmaceutically suitable excipients may be, for example, solid, semi-solid or liquid carriers, emulsifiers or dispersants, preservatives, anti-oxidants, UV absorbers. The concentration of active ingredients according to the invention is from 1 to 90% by weight, preferably from 5 to 50% by weight.
The dosage units of the active ingredients according to the invention may consist of, for example, 1, 2, 3 or 4 individual doses or xc2xd, ⅓ or xc2xc of an individual dose. An individual dose preferably contains the amount of active ingredient given on one administration, which usually corresponds to all, a half or a third or even a quarter of a daily dose.
Creams, pastes, ointments and gels may comprise, beside the active ingredient(s), carriers known to the person skilled in the art, for example waxes, paraffins, starches, vegetable and animal fats, cellulose derivatives, tragacanth, silicic acid, talcum, zinc oxide, bentonites, silicones, polyethylene glycols.
Sprays and powders may comprise, besides the active ingredient(s), carriers known to the person skilled in the art, for example lactose, talcum, silicic acid, aluminium hydroxide, calcium silicate or polyamide powder or mixtures thereof. Sprays may comprise, in addition, propellants, for example chlorofluorocarbons.
Suppositories may comprise, besides the active ingredients, carriers known to the person skilled in the art, for example polyethylene glycols, fats or mixtures thereof.
The present invention relates also to antibody conjugates comprising one or more tumour-specific antibodies and one or more active ingredients according to the invention, which can be cleaved under tumour-specific physiological conditions in the area surrounding the tumour or in the interior of the tumour. Those antibody conjugates may be packed in liposomes.
Local administration of the active ingredients according to the invention may be carried out by means of micro-machines.
In order to obtain better, locally relevant active ingredient concentrations and for greater tolerability, the active ingredients according to the invention may be packed in liposomes.
If advantageous for treatment of the tumour disease or infection or for the general condition of the patient or of the patient""s family, combinations with other active ingredients of use to the patient may be administered simultaneously or at different times.
The present invention also encompasses the use of the described active ingredients and pharmaceutical compositions comprising one or more active ingredients for the purpose of treating atypical tissues, in humans and livestock, that hinder or interfere with the course of normal biological functions.
Such tissues may be, for example:
benign and malignant tumours that are solid or cystic in nature, adenomas, cystadenomas, papillomas, adenocarcinonmas including those of the cirrhotic type, basal cell carcinomas, sarcomas, for example fibrosarcoma, liposarcoma, lympho-sarcoma, rhabdomyosarcoma, myxosarcoma, chondrosarcoma, reticulum cell sarcoma, Hodgkin""s disease, embryonal tumours, for example neuroblastoma, nephroblastoma, teratoma, adamantinoma, retroblastoma, haemangioma, chordoma, odontoma, craniopharyngoma, hamartomas, for example lymphoangioma, exostoses, neurofibrantosis, melanomas, lymphomas, hepatoblastomas, mammary carcinomas, cervical carcinoma, choriocarcinoma, adenoacanthoma, androblastoma, leiomyoma, arrhenoblastoma, Sertoli""s cell tumour, theca and granulosa cell tumour, germinoma and seminoma, ovarian and vulvar carcinoma, urinary bladder and prostate carcinoma, tumours caused by schistosomiasis, astrocytoma, ependymogliomas, glioblastomas, medulloblastoma, oligodendroglioma, spongio-blastoma, meningeoma and also tumours of Schwann""s sheath cells, pinealoma, haemangioblastoma, osteoclastoma, Ewing""s tumour, multiple myeloma, mycosis fungoides, Burkitt""s tumour, leukaemias, for example acute and chronic lymphatic leukaemia, acute and chronic granulocytic leukaemia, acute and chronic monocytic leukaemia and also stem cell leukaemia, basalioma, fibroma, myoma and also metastases of any form of tumour that are accessible by surgical intervention in the form of a local injection.
Specific examples of pyrroloimidazole derivatives according to the invention that may be mentioned are:
3-(1-cyclohexyl-1H-imidazol-5-yl)-1-methyl-1H-indole 
[M+H]+. Found ISP-TOF-MS: 279.3882 [M+H]+; 302.3782 [M+Na]+.
5-(benzyloxy)-3-(1-cyclohexyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-c]pyridine 
xe2x80x83[M+H]+. Found ISP-TOF-MS: 373.4739 [M+H]+; 395.4639 [M+Na]+.
3-(1-cyclohexyl-1H-imidazol-5-yl)-1H-indole 
xe2x80x83[M+H]+. Found ISP-TOF-MS: 266.3610 [M+H]+; 288.3511 [M+Na]+.
The compounds according to the invention are prepared in a manner customary per se, for example in accordance with van Leussen et al., J. Org. Chem., 42, 1977, 1153-1159.
By way of example, a general procedure for the synthesis of 1,5-disubstituted imidazole derivatives (Examples 1-2) is described below:
6 mmol of amine and 6 mmol of aldehyde are pre-condensed in 3 ml of dichloromethane overnight to form the Schiff""s base, the dichloromethane is drawn off and 3 ml of methanol are added to the residue. To the resulting suspension there are added 6 mmol of solid TOSMIC and 1 equivalent of base and the mixture is boiled under reflux at 80xc2x0 C. for four hours. The solvent is drawn off and the crude product is purified by means of preparative HPLC.